Anemia is defined by the World Health Organization's as hemoglobin concentration <13.0 g/dl in men and <12.0 g/dl in women. Approximately nine percent of the general adult population meets this definition of anemia. The prevalence of anemia ranges from less than 10% among patients with mild heart failure to more than 50% for those with advanced disease.
Anemia has been shown to be a powerful predictor of rehospitalization rates and survival in chronic heart failure. Most studies have shown a linear relationship between hematocrit or hemoglobin and survival with the SOLVD (Studies of Left Ventricular Dysfunction) trial reporting a 2.7% increase in the adjusted risk of death per 1% reduction in hematocrit and the PRAISE (Prospective Randomized Amlodipine Survival Evaluation) trial describing a 3% increase in risk for each 1% decline in hematocrit. The significance of anemia among patients hospitalized with acute decompensated heart failure has been examined. Felker et al. retrospectively analyzed the OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) results and found that hemoglobin level independently predicted adverse events, even after adjustment for other covariates. For every 1 g/dl decrease in admission hemoglobin value, a 12% increase in the probability of death or rehospitalization within 60 days of treatment was observed. Recently, the same investigators studied anemia in patients with heart failure and preserved systolic function. Anemia was once again found to be independently associated with adverse outcomes (adjusted hazard ratio: 1.6 to 1).
Chemotherapy-induced anemia (CIA) is a frequent complication in cancer patients receiving conventional myelosuppressive chemotherapy. Anemia affects up to 90% of cancer patients. The relative risk of death in patients with cancer has been determined to increase by 65% in the presence of anemia. Anemia as an independent prognostic factor for survival in patients with cancer: a systematic, quantitative review. Caro J J, Salas M, Ward A, Goss G, Cancer. 2001; 91:2214-2221.
In the case of Hodgkin's lymphoma, a cancer that is currently curable in approximately two thirds of patients, a hemoglobin level of less than 10.5 g/dl at the time of diagnosis is one of seven risk factors. The hemoglobin level is the strongest of three risk factors at relapse. There is a statistically significant difference in overall survival time between females having a hemoglobin level of less than 10.5 g/dl and females having a hemoglobin level of greater than 10.5 g/dl. There is also a statistically significant difference in overall survival time between males having a hemoglobin level of less than 12 g/dl and males having a hemoglobin level of greater than 12 g/dl.
The glycoprotein hormone erythropoietin (EPO) is the principal factor responsible for the regulation of red blood cell production. EPO acts in concert with other factors to stimulate the proliferation and maturation of responsive bone marrow erythroid precursors. EPO affects expansion of progenitor cells by repressing apoptosis (programmed cell death) and by acting as a mitogen to increase production. EPO, along with other factors, also decreases the maturation time of red blood cells in the bone marrow.
Erythropoeitic agents have been shown to reduce the need for blood transfusions and their associated complications in cancer patients undergoing chemotherapy, as demonstrated by several clinical trials. Daily subcutaneous administration of EPO stimulation therapy administration at a dose of 5000 IU increases hemoglobin levels and reduces transfusion requirements in chemotherapy-induced anemia, especially during platinum-based chemotherapy. (Oberhoff et al. (1998) Ann Oncol 9:255-260.) However, it is estimated that 30% to 50% of patients undergoing chemotherapy and receiving EPO stimulation therapy treatment are hyporesponsive or refractory to the recombinant EPO therapy. (J. Glaspy (2005) Expert Opin. Emerging Drugs 10:553-567.) In addition, synthetic EPO is known to have serious issues. Blood transfusions are also associated with negative consequences, such as iron overload which can cause cancer and/or death due to end-stage organ failure.
EPO is produced primarily in the kidney by endothelium of peritubular capillaries in the renal cortex. Additionally, the liver, macrophages in the bone marrow, and astrocytes in the central nervous system (CNS) make small amounts of EPO.
Various techniques are described herein for providing electrical stimulation to increase the production and efficacy of erythropoietin. Such techniques are optionally implemented, for example, in patients suffering from anemia from a variety of etiologies.